This K08 career development award will facilitate the development of the PI into a clinician scientist with an independent research program focused on antibody mediated neurological disorders. The scientific program in this grant focuses on a disorder defined by antibodies to Caspr2, a protein expressed on axons in the central and peripheral nervous systems. The PI and his coworkers have recently reported that auto antibodies previously attributed to potassium channels actually target two potassium channel associated proteins, LGI1 and CASPR2 (Lai et al., 2010; Lancaster et al., 2011). Patients with antibodies to Caspr2 usually have encephalitis and/or peripheral nerve hyper-excitability. While patients with Caspr2 antibodies respond to immunotherapy, most have persistent cognitive disability. Genetic mutations in the gene encoding Caspr2 have been associated with Autism and other intellectual disabilities. During the 5 years of the award period, the mechanisms of antibodies to Caspr2 will be explored in order to guide research into new therapies, and to better understand the related genetic disorders. Aim 1 will explore the domains on the Caspr2 protein targeted by the antibodies and how these antibodies disrupt the interaction of Caspr2 with other neuronal proteins. Aim 2 will explore the effects of Caspr2 antibodies on central and peripheral nervous system axons. And Aim 3 will examine the factors protecting nerve axons from auto- antibodies. This will lead to improved treatments for these patients and better understanding of the functions of Caspr2. The PI will be guided by three mentors with distinct areas of expertise that are necessary to complete this project: Dr. Joseph Dalmau (antibody mediated disorders of the nervous system), Dr. Steven S. Scherer (peripheral nerve anatomy and histology) and Dr. Rita Balice-Gordon (synaptic physiology and anatomy). The scientific work will be completed in the laboratories of Drs. Schere and Balice-Gordon, which occupy adjacent space at the University of Pennsylvania. A training plan to assist the PI in developing new research skills is an integral part of this application. These skills will be acquired through specific course work, through hands on training by his mentors, and through presentation of his scientific work at meetings. Specific scientific skills include studies of immunology, auto-immune disorders, synaptic physiology and anatomy, and peripheral nerve anatomy and physiology. Since this project involves both human subjects and laboratory animals, specific training in the ethical concerns involved in both areas is integrated into the training plan. PUBLIC HEALTH RELEVANCE: Patients with auto antibodies to Caspr2 may have encephalitis (seizures, cognitive impairment) and/or peripheral nerve hyper excitability (resulting in debilitating muscle spasms). Genetic mutations in Caspr2 may cause autism and other intellectual disabilities. This project will explore the mechanisms of Caspr2 antibodies in order t find better therapies and to understand the role of Caspr2 in neuronal function.